Recently, we have obtained direct evidence linking senile plaques and neurofibrillary tangles, the two hallmark lesions in Alzheimer's disease (AD). We cultured hippocampal neurons obtained from wild type, tau knockout, and human tau transgenic mice, and treated them with fibrillar AB. Morphological analysis indicated that neurons expressing either mouse or human tau proteins degenerated in the presence of AB. On the other hand, tau-depleted neurons showed no signs of degeneration in the presence of AB. These results suggest that tau is essential to AB-induced neurodegeneration. However, the mechanism by which tau mediates Aa toxic effects in central neurons are largely unknown. Most of the research effort in the field has been focused on the role of tau phosphorylation in neurite degeneration. We propose an alternative mechanism by which tau could mediate AB-induced neurite degeneration. We hypothesize that the deposition of fibrillar AB results in the cleavage of tau proteins. Truncated tau may contribute to neuronal cell death associated with neurodegeneration in central neurons. To test this hypothesis we propose to: 1) determine whether AB deposition induces cleavage of tau proteins; 2) identify the proteases responsible for tau cleavage in the presence of fibrillar AB; 3) determine to what extent tau cleaved fragments mediate AB neurotoxicity; and 4) determine whether factors capable of preventing Aa-induced tau cleavage prevent neuronal degeneration followed by cell death. The proposed experiments will be carried out using mature primary cultures of hippocampal neurons and AD animal models. A combination of techniques including Western blot analysis, in vitro protease assays, site-directed mutagenesis, and the suppression of protein expression by means of antisense oligonucleotides or siRNA will be used.